Methods for relieving pain

ABSTRACT

CHEMICAL COMPOUNDS OF THE FORMULA: IN WHICH X AND Y, WHICH MAY BE THE SAME OR DIFFERENT, EACH REPRESENT A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HYDROXY, HALOGEN, LOWER ALKYL, LOWER ALKOXY OR SULFONAMIDO AND R1 AND R2, WHICH MAY BE THE SAME OR DIFFERENT, REPRESENT HYDROGEN OR LOWER ALKYL. SAID COMPOUNDS HAVE DEMONSTRATED VALUABLE ANALGESIC PROPERTIES IN STANDARD LABORATORY ANIMALS.   QUINOXALINE   2-R1,3-R2,9-(O=),X,Y-2,3-DIHYDRO-9H-ISOXAZOLO(3,2-B)-

United States Patent METHODS FOR RELIEVING PAIN David B. Reisner, Highstown, Bernard J. Ludwig, North Brunswick, Frank M. Berger, Princeton, and Robert D. Sofia, Willingboro, NJ assignors to Carter-Wallace, Inc., New York, N.Y.

No Drawing. Continuation-impart of application Ser. No. 79,311, Oct. 8, 1970, now Patent No. 3,681,350, dated Aug. 1, 1972. This application July 21, 1972, Ser. No.

Int. Cl. A61k 27/00 US. Cl. 424-251 4 Claims ABSTRACT OF THE DISCLOSURE Chemical compounds of the formula:

M H Y N H R2 in which X and Y, which may be the same or different, each represent a member selected from the group consisting of hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or sulfonamido and R and R which may be the same or ditferent, represent hydrogen or lower alkyl. Saidcompounds have demonstrated valuable analgesic properties in standard laboratory animals.

This application is a continuation-in-part of application Ser. No. 79,311, filed Oct. 8, 1970, now US. Pat. 3,681,350, issued Aug. 1, 1972.v

' (3,2-b)quinazolin9-one as well as novel substituted 2,3-

dihydro-9H-isoxazolo(3,2-b)quinazolin-9-ones which are useful pharmacologically because of their aforesaid type of activity. Other objects of the invention will be apparent to one skilled in the art, and still other objects will become apparent hereinafter.

3,773,953 Patented Nov. 20, 1973 The compounds of the present invention are represented by the following general formula:

0 x II I N H 2 wherein X and Y, which may be the same or difierent, each represent a member selected from the group consisting of hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy and sulfonamido and R and R which may be the same or different, represent hydrogen or lower alkyl. As used throughout the instant specification and the appended claims, the terms lower alkyl and lower alkoxy shall mean alkyl and alkoxy radicals containing from 1 to 6 carbon atoms.

The compounds of the present invention can be prepared in accordance with any one of the following methods:

The following methods of preparation and examples are given by way of illustration only and are in no event to be construed as limiting.

METHOD A An isatoic anhydride, prepared from an anthranilic acid and phosgene, is allowed to react with the sodium or potassium salt of an appropriate 3-is0xazolidinone, prepared according to known methods, in water or an organic solvent such as dimethylformamide, pyridine, acetonitrile, Xylene, chloroform or a mixture of water and an organic solvent, such as described above, according to the following reaction scheme:

0 N----0 o lw mm =0 H N H R2 Y N R2 H wherein X, Y, R and R are as hereinbefore defined.

METHOD B An appropriate 3-isoxazolidinone, prepared from an acid halide of a 3-halogenoalkanoic acid and hydroxylamine in the presence of alkali in water, is reacted in situ with an appropriate isatoic anhydride with or without the addition of an organic solvent, such as employed in Method A, according to a reaction scheme similar to that of Method A.

METHOD C An ester of a o-(3-chloropropionamido)benzoic acid, such as prepared from an ester of anthranilic acid and an acid halide of a 3-chloroalkanoic acid, is reacted with hydroxylamine in the presence of alkali in water and/or a lower alkyl alcohol according to the following reaction scheme:

e C00 alkyl X ll HzNOH a 0 NHCOCHCHCI N 1 Y H R2 RzRr wherein X, Y, R and R are as hereinbefore defined.

METHOD D EXAMPLE IV .1

An o-aminobenzohydroxamic acid is reacted with an 3 methyl 2,3 dihydro-9H-isoxazolo(3,2-b)quinazolinacid halide of a 3-halogenoalkanoic acid in the presence 9-one was prepared following the procedure set forth of alkali in water and/or an alcohol according to the in Method B above 7 following reaction scheme: 600 ml. of aqueous solution containing 31.2 grams of O x CONHOH ClCHCHCOCl b No R1 8S l M 2 RJLRZ N H R2 Y Y wherein X, Y, R and R are as hereinbefore defined. sodium hydroxide was cooled at 0" C; and 27.2 grams of The invention is further illustrated by the following hydroxylamine hydrochloride was added. To the resulting examples. solution, 49.3 grams of 3-chloroisobutyryl chloride was EXAMPLE I added dropwise with coolingand stirring. The mixturev was stirred at room temperature for 2 hours. 32 grams of 50% aqueous solution of sodium hydroxide was added, and the mixture was then heated at 65 C. for one hour,

Preparation of 2,3-dihydro-9H-isoxazolo(3,2-b) quinazolin-9-one Following the Pmcsdllre set forth in Method a $0111- allowed to cool to room temperature and treated withtion of 10 grams of the sodium salt of 3-isoxazolidinone 40 grams of isatoic h id chl rof (200 -ml;)i in 200 of water was adjusted to P 3 with y was added and the mixture was stirred overnight. The chloric acid and 8.1 grams of isatoic anhydride was added t layers r separated e d 'the eou layer was portiohwise- The mixtul's was stirred Overnight at room washed with chloroform. The chloroform solutions were temperature and then extracted with three 100 ml. porcombined, dried, and evaporated to dryness leaving 51 tions of chloroform. The chloroform solutions were comgrams f an il, Th il w t at dwith, absolute ethanol billed, dried, and evapm'atsd y The crude P containing hydrogen chloride 'gas' and the solid was re-' uct (6.4 grams) was recrystallized from xylene giving 4.5 d, t d ith dilute ammonium hydroxide, and grams of P fi ,3-d y )q extracted into chloroform. The chloroform solution was azolin-9-one. washed with a saturated sodium chloride solution, dried,

. EXAMPLE l1 and evaporated to dryness giving 12 grams of 3-methyl- 2,3 dihydro-9H-isoxazolo(3,2-b)quinazolin 9 one having a melting point of 143-l46 C.

EXAMPLE V 2,3-dihydro-9H-isoxazolo(3,2-b)quinazolin-9-one was prepared using the procedure of Method C above (A) To a cooled solution of 12 grams of methyl anthranilate in pyridine, 10.1 grams of 3-chloropropionyl In accordance the Procedures Quflmed 1n Methodh chloride was added dropwise. The mixture was stirred for f" 3 methyl'z3dlhydro9Hlsoxazolo(33d?)(111111 two hours with cooling and then evaporated under re- 40 azohn9'one was Prepared as follows duced pressure. The oil was dissolved in chloroform, To a solution of grams of o-amihohehzohydroxamic washed with saturated sodium chloride solution, dried, acid in 50 Of Py was added dropwise grams and evaporated to dryness under reduced pressure. The of 3chlol'oisohlltyfyl Chloride and the Solution a oil that crystallized on standing was recrystallized [first stirred at room tempefatllfe'for hours- The Py fro ethyl ther d th f isopropyl h Th dwas removed in vacuo and the residue was treated with net, methyl o-(3-chloropropionamido)benzoate melted t water and ether and the resulting mixture was adjusted to 87-90 C. and gave the following analysis: Calculated P The ether t o Was Separated, dried and evapofor C H ClNO (percent): C, 54.67; H, 5.01; CI, 14,67; rated to dryness. The residue was heated on a steam bath N, 530. Found (percent): C, 54.86; H, 5.08; Cl, 14,71; for one-half hour with an aqueous solution containing N, 5,73, one equivalent of sodium hydroxide. The mixture was (3) T a i t f i d water were dd d 1 5 cooled and extracted with chloroform and the chlorograms f 50% aqueous l i of di h d id form solution was dried and evaporated under reduced 0.7 gram of hydroxylarnine hydrochloride and a solution pressure- The solid residue was recrystallized from ethyl of 2.4 grams of methyl o-(3-chloropropionamido)benzoacetate giving Y Y ate in ethanol. The mixture was filtered and the filtrate q melting P0111t was concentrated to remove the alcohol. The water solu- EXAMPLE VI tion was extracted with chloroform and the chloroform solution was concentrated by evaporation. The residue was recrystallized from ethyl ether-ethyl acetate to give In accordance with the procedures outlined in Method B above, 2 methyl 2,3 dihydro-9H-isoxazolo(3,2-b)

2,3-dihydro-9H-isoxazole(3,2-b)quinazolin-9-one. quinazcfun-g'one was Prepared as follows Following the procedure described in Example IV em- EXAMPLE IH ploying 64 grams of 3 -chl orobutyryl chloride and 60 Preparation of 7-chloro-2,3-dihydro-9H-isoxazolo(3,2-b) grams lsatolc anhydrfde m mm of the grains of quinazofin 9 one 3-chloro1sobutyryl chloride and 40 grams of 1sato1c an- 65 hydride respectively, 29.3 grams of 2-methyl-2,3-dihydro- Following the procedure set forth in Method A, a sus- 9 .i 1 3 2 )quinaZo1in 9 one was obtained.

pension of 8.0 grams of the sodium salt of 3-isoxazolidin- Th ti compounds of th present in ention can be 0116 grams s'chlofolsatolc anhydride in 150 used in the free base form or in the form of an acid addiof dlmethylformamlde wasstlffed and heated at 80 tion salt thereof with a pharmacologically acceptable 90 C. for two hours. The mlxture was filtered and the id, A u ed herein the term pharmacologically actiltrate evaporated to dryness. The residue was dissolved ceptable aci shall mean organic and inorganic acids in chloroform and the chloroform solution was washed such as hydrochloric, phosphoric, sulfuric, citric, acetic, with water and dried. After evaporation of the solvent, tartaric, and th like,

the residue, 7 chloro 2,3 dihydro-9H-isoxa-zolo(3,2-b) The following examples illustrate the preparation of quinazolin-9-one, was recrystallized from ethanol. acid addition salts useful in the present invention.

7 (B) -ch1oro-4-methylisatoic anhydride grams of 4-methylisatoic anhydride in 300 ml. of acetic acid was treated with 10 grams of sulfuryl chloride. The mixture was heated at about 60 C. for several hours. Solid was removed by filtration, washed with water, and air dried. The solid weighed 11.3 grams and melted with decomposition at 228 289 C. and analyzed as follows: Calculated for C H ClNO (percent): C, 51.08; H, 2.86; Cl, 16.75; N, 6.62. Found (percent): C, 50.89; H, 2.86; Cl, 16.60; N, 6.59.

This anhydride was used to prepare Compound 10 of Table 1.

One or a mixture of the compounds of the present invention in their free form or as their pharmacologically acceptable acid addition salts can be administered to warm-blooded animals in a variety of unit dosage forms, such as tablets, capsules or injectable solutions. In general, the compounds of the present invention are incorporated with suitable liquid or solid pharmaceutical carriers such as water, propylene glycol, polyethylene glycol, saline, acacia starch, glucose, lactose, sucrose, gelatin, mixtures thereof and the like to form unit dosage forms suitable for administration by injection or for oral administration.

The compounds of the present invention exhibit useful analgesic properties when evaluated in standard laboratory animals by the Randall-Selitto Test, the Haifner Tail Pinch Test and the usual hot plate analgesic test.

The Randall-Selitto procedure is preferred for the purpose of demonstrating the analgesic properties of the compounds of the present invention because it yields more quantative information. The procedure used is based upon the method described by Randall and Selitto, in Arch. Intl. Pharmacodyn., 111: 409, 1957.

Nonfasted male Charles River rats weighing 90 to 130 grams were injected in the right hind paw with 0.1 ml. of 20% brewers yeast suspension in distilled water. One hour later test drugs were administered orally in such a concentration permitting 0.5 ml. of the drug solution (in 1% acacia) to be given per 100 grams of body weight. The pain threshold was measured one hour after drug administration by applying a steadily increasing pressure of 14 grams per second to the infiammed paw which was continuously monitored by an indicator moving along a linear scale (Analgesy-Meter, Ugo Basile, Milan, Italy). The rat paw was positioned on a Teflon platform and force applied to the surface via a Teflon cone. The end point or pain threshold was defined as the pressure (in grams) necessary to cause the animals to struggle and/or vocalize.

The data from these experiments were analyzed in the following manner. First, the mean (+S.E.) pain thresholds were calculated for each vehicle and drugtreated group. The percent change (increase or decrease) in mean pain threshold was obtained by dividing the value of the control group into that of the drug-treated group. Secondly, rats in the drug-treated groups were designated as displaying analgesic activity if the individual reaction threshold to pressure equalled or exceeded the control group mean threshold by two standard deviations of that mean (Swingle, et al., Proc. Soc. Exptl. Med., 1372536, 1971). Thus, the results are based on an all-or-none response and ED values calculated according to the method of Litchfield and Wilcoxon (I. Pharmacol. Exptl. Therap., 96:99, 1942). Table 2, which follows, sets forth the results obtained from an evaluation of a representative number of compound from Table l.

TABLE 2 Percent No. analincrease Compound Oral dose, gesic/ in pain No. mgJkg. No. tested threshold ED5u=2A (1.3-4-6) The foregoing examples and tables have been illustrative of the invention only and are not to be considered as placing any limitation on the invention. It is recognized that various departures may be made therefrom within the scope of the accompanying claims without departing from the principles of the invention.

What is claimed is:

1. A method of relieving pain in a warm-blooded animal which comprises administering systemically to said animal a pharmaceutically effective amount of a compound selected from the group consisting of a compound of the formula.

X 0 II Rl N H Y H R:

and an acid addition salt thereof in which X and Y, which may be the same or diflerent, each represent a member selected from the group consisting of hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or sulfonamido and R and R which may be the same or difierent are hydrogen or lower alkyl.

2.. The method according to claim 1 wherein said compound is 2,3 dihydro-9H-isoxazolo(3,2-b)quinazolin-9- one.

3. The method according to claim 1 wherein said compound is B-methyl 2,3 dihydro-9H-isoxazolo(3,2-b) quinazolin-9-one.

4. The method according to claim 1 wherein said compound is Z-methyl 2,3 dihydro 9H-isoxazolo(3,2-b) quinazolin-9-one.

References Cited UNITED STATES PATENTS 3,280,117 10/1966 Griot 260243 STANLEY I. FRIEDMAN, Primary Examiner 

